Following injury/stress cardiac output is diverted, provoking spanchnic hypoperfusion. Although our Trauma Center could not identify portal venous bacterial/endotoxin in trauma patients (bacterial translocation), we do propose that the post-injury splanchnic circulation serves as a "priming bed" for circulating neutrophils. Post-injury shock renders the injured patient (with projects IA and IC) at risk for MOF by 1) priming circulating PMN's for cytotoxicity (CD11b/CD18 expression, endothelial, superoxide production, degranulation, cytokine release) and 2) activating microvascular endothelium (Projects VI and VIII) for primed PMN adherence (E-selection ICAM-1). Traditional anti- neutrophil and anti-cytokine (Project VII) therapies have proven disappointing. Two years ago we proposed to prevent the ischemic gut from "priming" PMN's and thus provoking inflammation/MOF by intervening at the level of intracellular PMN signaling. In this current application, we wish to extend these observations and now propose gut phospholipase A2 as a proximal inflammatory signal that activates P38 MAP kinase inducing both 1) PMN "priming" and 2) distant organ endothelial expression of contraligands for primed neutrophils. We also postulate that receptor dependent P38 MAP kinase activation requires cytoskeletal remodeling (with Project VIII) and that hyperosmolar resuscitation (osmolar stress) promotes actin depolymerization/restructuring that prevents PMN priming by inhibiting P38 MAPK activation. Consequently, we hypothesize that hyperosmolar resuscitation of the injured patient with attenuate systemic PMN priming and reduce neutrophil adherence to endovasculature, thus reducing the incidence of MOF. Elucidation of the link between intracellular signals and cytoskeletal trafficking may suggest novel interventions into the modification of PMN:endovascular responses in disease hyperinflammatory syndromes.